M-Ras/Shoc2 signaling modulates E-cadherin turnover and cell-cell adhesion during collective cell migration

Proceedings of the National Academy of Sciences of the United States of America
Pradeep KotaDeborah K Morrison

Abstract

Collective cell migration is required for normal embryonic development and contributes to various biological processes, including wound healing and cancer cell invasion. The M-Ras GTPase and its effector, the Shoc2 scaffold, are proteins mutated in the developmental RASopathy Noonan syndrome, and, here, we report that activated M-Ras recruits Shoc2 to cell surface junctions where M-Ras/Shoc2 signaling contributes to the dynamic regulation of cell-cell junction turnover required for collective cell migration. MCF10A cells expressing the dominant-inhibitory M-RasS27N variant or those lacking Shoc2 exhibited reduced junction turnover and were unable to migrate effectively as a group. Through further depletion/reconstitution studies, we found that M-Ras/Shoc2 signaling contributes to junction turnover by modulating the E-cadherin/p120-catenin interaction and, in turn, the junctional expression of E-cadherin. The regulatory effect of the M-Ras/Shoc2 complex was mediated at least in part through the phosphoregulation of p120-catenin and required downstream ERK cascade activation. Strikingly, cells rescued with the Noonan-associated, myristoylated-Shoc2 mutant (Myr-Shoc2) displayed a gain-of-function (GOF) phenotype, with the cells ex...Continue Reading

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Citations

Jun 12, 2019·Nature Communications·Greg G JonesPablo Rodriguez-Viciana
Oct 24, 2019·Physical Review. E·Alexis Grau RibesLaurence Rongy
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Oct 25, 2020·Journal of Cell Science·Sarah J KurleyAlbert B Reynolds
Feb 3, 2021·Molecular and Cellular Biology·Jason J Kwon, William C Hahn

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Methods Mentioned

BETA
GTPases
BRET
coimmunoprecipitation
GTPase
myristoylation
fluorescence recovery after photobleaching
pull-down
immunoprecipitation
transfection

Software Mentioned

BRET
Scribble

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